Tay-Sachs and Sandhoff diseases are severe neurodegenerative disorders characterized by impaired GM2 ganglioside degradation as a consequence of beta-hexosaminidase A deficiency. Mutations in the HEXA and HEXB genes, which encode the subunits of beta-hexosaminidase A, cause Tay- Sachs and Sandhoff disease, respectively. In humans, the neurologic phenotype and neuropathology in the two diseases are very similar. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to Tay-Sachs and Sandhoff diseases. Mice homozygous for either the disrupted Hexa or Hexb gene were deficient in beta-hexosaminidase A and accumulated GM2 in their brains. However, unlike Tay-Sachs and Sandhoff disease patients, the Hexa and Hexb "knock-out" mice displayed very different phenotypes. The Hexa knock-out mice had a normal life span (about 2 years) and showed no neurologic abnormalities. In contrast, the Hexb knock-out mice were severely affected. Beginning at about 3.5 months these animals showed progressive gait abnormalities, muscle wasting and spasticity. By 5 months the animals displayed nearly complete limb paralysis. Consistent with the different phenotypes were athe number and distribution of storage neurons in the two types of mutant mice. In the Hexb knock-out mice storage was observed in almost all neurons in the central nervous system. In contrast, in the Hexa knock-out mice storage was restricted to certain regions of the brain. In light of the phenotypic difference, it is notable the significant storage was found in cerebellar Purkinje cells and in the spinal cord motor neurons in the Hexb but not the Hexa knock-out mice. Furthermore, we have found that phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.